**1. Introduction**

Systemic lupus erythematosus (SLE) is one of the most prevalent systemic autoimmune diseases caused by a dysfunctional immune system. In the SLE-affected individuals, autoantibodies are generated against tissue antigens, including nuclear, cytoplasmic, phospholipid-associated, and cell-membrane antigens—major constituents of different cell types residing in tissues and organs of the human body [1]. The binding of autoantibodies with tissue antigens generates immune complexes, which may be deposited inside tissues and organs over time. These immune complexes elicit a cascade of immune responses that result in severe inflammation and destruction of tissue architecture, leading to multiorgan dysfunction and premature mortality [2].

SLE is a long-term multisystem autoimmune rheumatic disease that can affect the skin, joints, kidneys, lungs, heart, and central nervous system. Clinical manifestations range from mild to severe and life-threatening diseases, which could

be associated with poor outcomes, including morbidity, poor quality of life, and premature mortality. There is no cure for SLE, and the management is guided by organ system involvement, flare prevention, managing comorbidities, and reducing damage accumulation. The clinical signs and course of the pathology of SLE can be altered through lifestyle alteration, such as avoiding sunlight and diet modifications. The incidence and prevalence of SLE have increased in the last few decades, possibly due to increased awareness and the ability to diagnose milder forms of SLE [3]. Studies indicate that SLE has shown strong ethnicity and gender biases. Certain ethnic groups such as those with African and Asian ancestry are more predisposed to the development of SLE. While the incidence of SLE differs between the different ethnic groups, it is interesting to note that the incidence of SLE is higher in females than in males, across all groups of ethnicities [4, 5]. Pregnant women with SLE have an increased risk of recurrent miscarriages, fetal retardation, and stillbirths especially if they are positive for antiphospholipid antibodies. The babies born to SLE mothers are at a 3% risk of having neonatal lupus especially if they are positive for anti-RO and/or anti-LA antibodies [6].

SLE is a complex disease with poorly defined etiology. Several studies have reported a strong correlation between disease incidence and certain genetic and environmental factors. About 7% of childhood-onset SLE show Mendelian inheritance and is associated with defects in genes involved in the clearance of necrotic and/or apoptotic cell debris, pathways that protect against autoimmune response against autoantigens, and those involved in autoreactive lymphocyte generation and maintenance [7–10]. Hormones are a significant underlying factor responsible for genderbiased SLE development. Specifically, estrogen and estrogen receptor signaling mediates SLE through positive regulation of CREMα transcription factor, favoring the generation of CD4+ T effector cells and double-negative T cells [11]. Several environmental factors have been associated with an increased risk of SLE. However, the time duration of exposure and dosage is not well-defined [12–14]. Particulate matter in the air, including cigarette smoke, induces oxidative stress and can damage endogenous DNA, and cellular proteins are known to trigger SLE development [15, 16]. Exogenous hormone uses, such as oral contraceptives and hormone replacement therapy, have been positively linked with SLE onset [17]. The involvement of cardiovascular disease in patients with SLE can increase the risk of mortality [18]. Renal failure and sepsis are the significant causes of mortality in patients with SLE [19]. Furthermore, autoimmune vascular injury increases the risk of atherosclerosis and coronary artery diseases in SLE patients [20].

Over the past two decades, the understanding of SLE pathogenesis and treatment has improved. Significant progress has been made in uncovering the molecular events that trigger SLE pathogenesis and exploring novel treatment options, including newly approved biologics. In this chapter, we discuss the advances in the pathogenesis of SLE and emerging treatment options.
